Whole-exome sequencing reveals a heterozygous LRP5 mutation in a 6-year-old boy with vertebral compression fractures and low trabecular bone density

Juvenile osteoporosis (JO) is characterized by bone fragility during development, low bone mass and absence of extraskeletal features. Heterozygous loss-of-function mutations in LRP5 have been found in a few patients, but bone tissue and bone material abnormalities associated with such mutations have not been determined. Here we report on a 6-year-old boy who presented with a history of seven low-energy long-bone fractures starting at 19 months of age and absence of extraskeletal involvement. Spine radiographs revealed multiple vertebral compression fractures. Despite tall stature (95th percentile), lumbar spine areal bone mineral density was low (z-score = − 3.2). Trabecular volumetric bone mineral density, measured by peripheral quantitative computed tomography at the distal radius, was low (z-score = − 5.1), but cortical thickness at the radial diaphysis was normal. Iliac bone histomorphometry demonstrated low bone formation activity in trabecular but not in cortical bone. Quantitative backscattered electron imaging showed normal material bone density in trabecular bone, but elevated results in the cortex. Whole-exome sequencing revealed a heterozygous insertion of a nucleotide in exon 12 of LRP5. This mutation had previously been reported in another JO patient and had been shown to lead to nonsense-mediated decay. Thus, heterozygous loss-of-function mutations in LRP5 can be associated with a bone formation deficit that affects mostly the trabecular compartment and can result in bone fragility during the first years of life.